Nerve stimulation and blocking for treatment of gastrointestinal disorders

ABSTRACT

At least one of a plurality of gastrointestinal disorders is treated by stimulating an enteric nervous system of a patient to enhance a functional tone of the enteric nervous system. A treatment includes electrically stimulating a vagus nerve of the patient at a stimulation site proximal to at least one site of vagal innervation of a gastrointestinal organ. The electrical stimulation includes applying a stimulation signal at the stimulation site. An optional proximal electrical blocking signal is applied to the vagus nerve at a proximal blocking site proximal to the stimulation site. The proximal blocking signal is selected to at least partially block nerve impulses at the proximal blocking site.

I. CROSS-REFERENCE TO RELATED APPLICATION

The present application is a continuation of U.S. patent applicationSer. No. 10/675,818 filed Sep. 29, 2003 and entitled “Enteric RhythmManagement”, now abandoned. The present application is also acontinuation-in-part application of U.S. patent application Ser. No.10/358,093 filed Feb. 3, 2003 and entitled “Method and Apparatus forTreatment of Gastroesophageal Reflux Disease (GERD)”, now abandoned. Thepresent application discloses and claims subject matter disclosed in thefollowing commonly assigned U.S. patent applications filed on the samedate as the present application and in the name of the same inventors:U.S. patent application Ser. No. 10/674,324, entitled “Nerve StimulationAnd Conduction Block Therapy”, now abandoned, and U.S. patentapplication Ser. No. 10/674,330, entitled “Vagal Down-Regulation ObesityTreatment”, now U.S. Pat. No. 7,489,969.

II. BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention pertains to treatments of disorders associated, at leastin part, with neural activity. These may include, without limitation,gastrointestinal, pancreo-biliary, cardio-respiratory and centralnervous system disorders (including neurological and psychiatric,psychological and panic disorders). More particularly, this inventionpertains to treatment of such disorders through management of neuralimpulse stimulation and blocking.

2. Description of the Prior Art

A. Functional Gastrointestinal Disorders (FGIDs)

Functional Gastrointestinal Disorders (FGIDs) are a diagnostic groupinghaving diagnostic criteria based on symptomatology, because thepathophysiology of these diseases is multifactorial with somepathophysiologic mechanisms in common. FGIDs are thought to be due toaltered autonomic nervous system balance and to be pathophysiologicalcombinations of: (1) abnormal GI motility; (2) visceralhypersensitivity; and, (3) brain-gut interactions. Tougas, “TheAutonomic Nervous System in Functional Bowel Disorders”, Gut, Vol. 47(Suppl IV), pp. iv78-iv80 (2000) and Drossman, “Rome II: A MultinationalConsensus Document on Gastrointestinal Disorders—The FunctionalGastrointestinal Disorders and the Rome II Process”, Gut, Vol. 45 (SupplII):II1-II5 (1999). The FGIDs of interest to the present invention arefunctional dyspepsia (dysmotility-like) and irritable bowel syndrome(IBS).

1. Functional Dyspepsia (Dysmotility-Like)

Functional dyspepsia (dysmotility-like), is diagnosed when a patient'ssymptoms, in the absence of other organic disease likely to explain thesymptoms, include persistent or recurrent pain or discomfort centered inthe upper abdomen that may be accompanied by upper abdominal fullness,early satiety, bloating or nausea. Talley et al., “Rome II: AMultinational Consensus Document on GastrointestinalDisorders—Functional Gastroduodenal Disorders” Gut, Vol. 45 (Suppl II),pp. I37-II42 (1999).

A spectrum of dysmotilities has been documented in patients withfunctional dyspepsia. These include delayed gastric emptying of solidsand liquids, reduced vagal tone, gastric dysrhythmias and impairedgastric accommodation. Furthermore, some studies have found goodcorrelation between symptoms and indices of dysmotility, while othershave not. Stanghellini V, et al., “Delayed Gastric Emptying of Solids inPatients with Functional Dyspepsia”, Gastroenterol, (1996)110:1036-1042. Undeland K A, et al., “Wide Gastric Antrum and Low VagalTone in Patients with Diabetes Mellitus Type 1 Compared to Patients withFunctional Dyspepsia and Healthy Individuals”, Dig Dis Sci, (1996)41:9-16. Tack J, et al., “Role of Impaired Gastric Accommodation to aMeal in Functional Dyspepsia”, Gastroenterol, (1998) 115:1346-1352.Wilmer A, et al., “Ambulatory Gastrojejunal Manometry in SevereMotility-like Dyspepsia: Lack of Correlation between Dysmotility,Symptoms and Gastric Emptying”, Gut, (1998) 42:235-242. Tack J, et al.,“Symptom Pattern and Gastric Emptying Rate Assessed by the Octanoic AcidBreath Test in Functional Dyspepsia” [abstract]. Gastroenterol, (1998)114:A301. Cuomo R, et al., “Functional Dyspepsia Symptoms, GastricEmptying and Satiety Provocation Test: Analysis of Relationships”, ScandJ Gastroenterol, (2001) 36:1030-1036. Sarnelli G, et al., “SymptomsAssociated with Impaired Gastric Emptying of Solids and Liquids inFunctional Dyspepsia”, Am J Gastroenterol, (2003) 98:783-788.

2. Irritable Bowel Syndrome (IBS)

The second FGID of interest, IBS, is diagnosed when a patient's symptomsinclude persistent abdominal pain or discomfort, in the absence of otherexplanatory organic disease, along with at least two of the following:relief of pain with defecation, onset of symptoms associated with achange in frequency of stools and/or onset of symptoms associated with achange in appearance/form of stools. Thompson W G, et al., “Rome II: AMultinational Consensus Document on GastrointestinalDisorders—Functional Bowel Disorders and Functional Abdominal Pain”,Gut, (1999) ;45(Suppl II):II43-II47.

In addition to colonic dysmotility, a number of other GI motilityabnormalities have been identified, including delayed gastric emptying,gastroparesis, and small intestine motility abnormalities. Vassallo M J,et al., “Colonic Tone and Motility in Patients with Irritable BowelSyndrome”, Mayo Clin Proc, (1992);67:725-731. Van Wijk H J, et al.,“Gastric Emptying and Dyspeptic Symptoms in the Irritable BowelSyndrome”, Scand J Gastroenterol, (1992);27:99-102. Evans P R, et al.,“Gastroparesis and Small Bowel Dysmotility in Irritable Bowel Syndrome”,Dig Dis Sci (1997);42:2087-2093. Cann P A, et al. “Irritable BowelSyndrome: Relationship of Disorders in the Transit of a Single SolidMeal to Symptoms Patterns”, Gut, (1983);24:405-411. Kellow J E, et al.,“Dysmotility of the Small Intestine in Irritable Bowel Syndrome”, Gut,(1988);29:1236-1243. Evans P R, et al., “Jejunal SensorimotorDysfunction in Irritable Bowel Syndrome: Clinical and PsychosocialFeatures”, Gastroenterol, (1996);110:393-404. Schmidt T, et al.,“Ambulatory 24-Hour Jejunal Motility in Diarrhea-Predominant IrritableBowel Syndrome”, J Gastroenterol, (1996);31:581-589. Simren M, et al.,“Abnormal Propagation Pattern of Duodenal Pressure Waves in theIrritable Bowel Syndrome (IBS)”, Dig Dis Sci, (2000);45:2151-2161.

A related finding is that patients with constipation-predominant IBShave evidence of decreased vagal tone, while diarrhea-predominant IBS isassociated with evidence of increased sympathetic activity. Aggarwal A,et al., “Predominant Symptoms in Irritable Bowel Syndrome Correlate withSpecific Autonomic Nervous system Abnormalities”, Gastroenterol,(1994);106:945-950.

There is no cure for IBS. Treatments include supportive palliative care(antidiarrheals, dietary modification and counseling).

A recently approved drug to treat selected patients with FGIDs istegaserod maleate sold under the tradename “Zelnorm®” by NovartisPharmaceuticals Corp., East Hanover, N.J., USA. The product literatureon Zelnorm recognizes the enteric nervous system is a key element intreating IBS. The literature suggests Zelnorm® acts to enhance basalmotor activity and to normalize impaired motility. Novartis productdescription, Zelnorm®, July 2002 (T2002-19). Zelnorm's approved use islimited to females with constipation-related IBS. It is for short-termuse only.

B. Gastroparesis

The third disease indication discussed here, gastroparesis (or delayedgastric emptying) is associated with upper GI symptoms such as nausea,vomiting fullness, bloating and early satiety. Gastroparesis can becaused by many underlying conditions. The most important, because ofchronicity and prevalence, are diabetes, idiopathic and post-surgical.Hornbuckle K, et al. “The Diagnosis and Work-Up of the Patient withGastroparesis”, J Clin Gastroenterol, (2000);30:117-124. GI dysmotilityin the form of delayed gastric emptying is, by definition, present inthese patients.

In patients with Type 1 diabetes mellitus and delayed gastric emptying,there appears to be a relationship between delayed gastric emptying andlow vagal tone. Merio R, et al., “Slow Gastric Emptying in Type 1Diabetes: Relation to Autonomic and Peripheral Neuropathy, BloodGlucose, and Glycemic Control”, Diabetes Care, (1997);20:419-423. Arelated finding is that patients with Type 1 diabetes have low vagaltone in association with increased gastric antral size, possiblycontributing to the dysmotility-associated symptoms seen in thesepatients. Undeland K A, et al., “Wide Gastric Antrum and Low Vagal Tonein Patients with Diabetes Mellitus Type 1 Compared to Patients withFunctional Dyspepsia and Healthy Individuals”, Dig Dis Sci,(1996);41:9-16.

The current treatments for gastroparesis are far from satisfactory. Theyinclude supportive care, such as dietary modification, prokinetic drugs,and; when required, interventions such as intravenous fluids andplacement of a nasogastric tube may be needed.

C. Gastroesophageal Reflux Disease (GERD)

The fourth indication, GERD, can be associated with a wide spectrum ofsymptoms, including dyspepsia, reflux of gastric contents into themouth, dysphagia, persistent cough, refractory hyperreactive airwaydisease and even chronic serous otitis media. Sontag S J, et al.,“Asthmatics with Gastroesophageal Reflux: Long Term Results of aRandomized Trial of Medical and Surgical Antireflux Therapies”, Am JGastroenterol, (2003);98:987-999. Poelmans J, et al., “Prospective Studyon the Incidence of Chronic Ear Complaints Related to GastroesophagealReflux and on the Outcome of Antireflux Therapy”, Ann Otol RhinolLaryngol, (2002);111:933-938.

GERD is considered to be a chronic condition for which long-term medicaltherapy and/or surgical therapy is often deemed necessary, insignificant part because esophageal adenocarcinoma is sometimes aconsequence of GERD. DeVault K R, et al., “Updated Guidelines for theDiagnosis and Treatment of Gastroesophageal Reflux Disease”, Am JGastroenterol, (1999);94:1434-1442. Lagergren J, et al., “SymptomaticGastroesophageal Reflux as a Risk Factor for Esophageal Adenocarcinoma”,New Engl J Med, (1999);340:825-831.

The underlying pathophysiological mechanisms in GERD are considered tobe transient lower esophageal relaxations (TLESRs) in the presence ofeither an inadequate pressure gradient between the stomach and theesophagus across the lower esophageal sphincter and/or low amplitudeesophageal activity at times when gastric contents do reflux into theesophagus. In addition, gastric distention is thought to be associatedwith an increase in TLESRs. Mittal R K, et al., “Mechanism of Disease:The Esophagogastric Junction”, New Engl J Med, (1997);336:924-932.Scheffer RC, et al., “Elicitation of Transient Lower OesophagealSphincter Relaxations in Response to Gastric Distension”,Neurogastroenterol Motil, (2002);14:647-655.

GERD is generally considered to be the result of a motility disorderwhich permits the abnormal and prolonged exposure of the esophageallumen to acidic gastric contents. Hunt, “The Relationship Between TheControl Of pH And Healing And Symptom Relief In Gastro-OesophagealReflux Disease”, Ailment Pharmacol Ther., 9 (Suppl. 1) pp. 3-7 (1995).Many factors are believed to contribute to the onset of GERD. Theseinclude transient lower esophageal sphincter relaxations (as previouslydescribed), decreased LES resting tone, delayed stomach emptying and anineffective esophageal clearance.

Certain drugs have had some effectiveness at controlling GERD but failto treat underlying causes of the disease. Examples of such drugs areH₂-receptor antagonists (which control gastric acid secretion in thebasal state) and proton pump inhibitors (which control meal-stimulatedacid secretion). Hunt, id. Both classes of drugs can raise intragastricpH to or about 4 for varying durations. Hunt, supra.

Surgery treatments are also employed for the treatment of GERD andinclude techniques for bulking the lower esophageal sphincter such asfundoplication and techniques described in U.S. Pat. No. 6,098,629Johnson et al, Aug. 8, 2000. Other surgical techniques include placementof pacemakers for stimulating muscle contractions in the esophagealsphincter, the stomach muscles or in the pyloric valve. U.S. Pat. No.6,104,955 to Bourgeois, U.S. Pat. No. 5,861,014 to Familoni.

A summary of GERD treatments can be found in DeVault, et al., “UpdatedGuidelines for the Diagnosis and Treatment of Gastroesophageal RefluxDisease”, Amer. J. of Gastroenterology, Vol. 94, No. 6, pp. 1434-1442(1999).

Notwithstanding multiple attempts at various types of treatment, GERDcontinues to be a serious disease proving to be difficult to treat byany of the foregoing prior art techniques. In view of the foregoing andnotwithstanding various efforts exemplified in the prior art, thereremains a need for an effective treatment for GERD. It is an object ofthe present invention to provide a novel treatment and novel apparatusfor the treatment of GERD.

D. Electrical Stimulation to Treat GI Disorders

Treatment of gastrointestinal diseases through nerve stimulation havebeen suggested. For example, U.S. Pat. No. 6,238,423 to Bardy dated May29, 2001 describes a constipation treatment involving electricalstimulation of the muscles or related nerves of the gut. U.S. Pat. No.6,571,127 to Ben-Haim et al. dated May 27, 2003 describes increasingmotility by applying an electrical field to the GI tract. U.S. Pat. No.5,540,730 to Terry, Jr. et al., dated Jul. 30, 1996 describes a motilitytreatment involving vagal stimulation to alter GI contractions inresponse to a sense condition indicative of need for treatment. The '730patent also uses a definition of dysmotility more restrictive than inthe present application. In the '730 patent, dysmotility is described ashyper- or hypo-contractility. In the present application, dysmotility isa broader concept to refer to all abnormalities of gastric emptying orbowel transfer regardless of cause. U.S. Pat. No. 6,610,713 to Traceydated Aug. 26, 2003 describes inhibiting release of a proinflammatorycytokine by treating a cell with a cholinergic agonist by stimulatingefferent vagus nerve activity to inhibit the inflammatory cytokinecascade.

A substantial body of literature is developed on nerve stimulation. Forexample, in Dapoigny et al., “Vagal influence on colonic motor activityin conscious nonhuman primates”, Am. J. Physiol., 262:G231-G236 (1992),vagal influence on colonic motor activity was investigated in consciousmonkeys. To block antidromic interference, the vagus was blocked viavagal cooling and a vagal stimulation electrode was implanted distal tothe vagal block. It was noted that vagal efferent stimulation increasedcontractile frequency and that the vagus has either a direct or indirectinfluence on fasting and fed colonic motor activity throughout thecolon, and that a non-adrenergic, noncholinergic inhibitory pathway isunder vagal control.

Colonic and gastric stimulation are also described in a number ofarticles associated with M. P. Mintchev. These include: Mintchev, etal., “Electrogastrographic impact of multi-site functional gastricelectrical stimulation”, J. of Medical Eng. & Tech., Vol. 23, No. 1 pp.5-9 (1999); Rashev, et al., “Three-dimensional static parametricmodeling of phasic colonic contractions for the purpose ofmicroprocessor-controlled functional stimulation”, J. of Medical Eng. &Tech., Vol. 25, No. 3 pp. 85-96 (2001); Lin et al., “Hardware—softwareco-design of portable functional gastrointestinal stimulator system”, J.of Medical Eng. & Tech., Vol. 27, No. 4 pp. 164-177 (2003); Amaris etal., “Microprocessor controlled movement of solid colonic content usingsequential neural electrical stimulation”, Gut, 50:pp 475-479 (2002) andRashev et al., “Microprocessor-Controlled Colonic Peristalsis”,Digestive Diseases and Sciences, Vol. 47, No. 5, pp. 1034-1048 (2002).

The foregoing references describe nerve stimulation to stimulatemuscular contraction in the GI tract. As will be more fully discussed,the present invention utilizes vagal stimulation to improve vagal tone(similar in concept to improving cardiac electrical tone through cardiacpacing) and/or to treat GI disorders by altering the nature of duodenumcontents by stimulation pancreatic and biliary output. The invention isalso applicable to treating other diseases such as neuropsychiatricdisorders.

Vagal tone has been shown to be associated with dyspepsia. Hjelland, etal., “Vagal tone and meal-induced abdominal symptoms in healthysubjects”, Digestion, 65:172-176 (2002). Also, Hausken, et al., “LowVagal Tone and Antral Dysmotility in Patients with FunctionalDyspepsia”, Psychosomatic Medicine, 55: 12-22 (1993). Also, decreasedvagal tone has been associated with irritable bowel syndrome.Heitkemper, et al., “Evidence for Automatic Nervous System Imbalance inWomen with Irritable Bowel Syndrome”, Digestive Diseases and Sciences,Vol. 43, No. 9, pp. 2093-2098 (1998).

Also, as will be discussed, the present invention includes, in severalembodiments, a blocking of a nerve (such as the vagal nerve) to avoidantidromic influences during stimulation. Cryogenic nerve blocking ofthe vagus is described in Dapoigny et al., “Vagal influence on colonicmotor activity in conscious nonhuman primates”, Am. J. Physiol.,262:G231-G236 (1992). Electrically induced nerve blocking is describedin Van Den Honert, et al., “Generation of Unidirectionally PropagatedAction Potentials in a Peripheral Nerve by Brief Stimuli”, Science, Vol.206, pp. 1311-1312. An electrical nerve block is described in Solomonow,et al., “Control of Muscle Contractile Force through IndirectHigh-Frequency Stimulation”, Am. J. of Physical Medicine, Vol. 62, No.2, pp. 71-82 (1983) and Petrofsky, et al., “Impact of Recruitment Orderon Electrode Design for Neural Prosthetics of Skeletal Muscle”, Am. J.of Physical Medicine, Vol. 60, No. 5, pp. 243-253 (1981). A neuralprosthesis with an electrical nerve block is also described in U.S.Patent Application Publication No. US 2002/0055779 A1 to Andrewspublished May 9, 2002. A cryogenic vagal block and resulting effect ongastric emptying are described in Paterson C A, et al., “Determinants ofOccurrence and Volume of Transpyloric Flow During Gastric Emptying ofLiquids in Dogs: Importance of Vagal Input”, Dig Dis Sci,(2000);45:1509-1516.

III. SUMMARY OF THE INVENTION

According to a preferred embodiment of the present invention, a methodand apparatus are disclosed for treating at least one of a plurality ofgastrointestinal disorders of a patient characterized at least in partby an altered autonomic balance or altered motility. The method includeselectrically stimulating an enteric nervous system of the patient toenhance a functional tone of the enteric nervous system.

Enteric rhythm management (ERM) treats GI diseases in which dysmotilityis thought to play a major role. This therapy is based on thephysiological actions of pancreatic exocrine secretion and bile on thecomposition (osmolality and pH) and the digestion (enzymatic activityand, in the case of fats, emulsification) of intraduodenal chyme,thereby presenting a novel approach to regulating the motility of the GItract and, in particular, gastric emptying and the digestion andpropulsion of chyme through the duodenum and into the jejunum and ileum.

ERM as a therapy for GI diseases involving dysmotility is based on thefollowing: (1) pacing the delivery of pancreatic exocrine secretion andbile can be used to either up- or down-regulate at least two aspects ofGI motility—gastric emptying and small bowel transit—by modulating theosmolality, the pH and the digestion, including emulsification asneeded, of intra-duodenal chyme; (2) pacing the efferent activity of theintra-abdominal vagus nerve as needed while blocking afferent activityof that same nerve as needed can be used to treat GI dysmotility inpatients with either increased or decreased vagal tone as a component oftheir disease; and, (3) treating GI dysmotility disorders can and oftendoes require flexibility in adjusting treatment algorithms based onsymptomatic response because of inter-patient differences with adiagnostic group and because of intra-patient variability over time.

The goals of enteric rhythm management in gastroparesis are: 1) toregulate the composition and digestion of duodenal chyme and, by sodoing, to facilitate gastric emptying through the modulatory effect ofduodenal chemo- and mechanoreceptors on the pylorus and 2) toup-regulate or down-regulate vagal tone to optimize gastricintestinalmotility and symptom relief.

In patient with GERD, ERM utilizing a physiologic enteric pacing devicewill, as described earlier, allow pacing of the delivery of pancreaticexocrine secretion and bile, thereby initiating pyloric relaxation,gastric emptying and consequent reduction in gastric distention, leadingto a decrease in the underlying mechanism of GERD, that is, TLESRs.

Kellow J E, et al., “Rome II: A Multinational Consensus Document onGastrointestinal Disorders—Principles of Applied Neurogastroenterology:Physiology/Motility-Sensation”, Gut, (1999);45(Suppl II):II17-II24.Paterson C A, et al., “Determinants of Occurrence and Volume ofTranspyloric Flow During Gastric Emptying of Liquids in Dogs: Importanceof Vagal Input”, Dig Dis Sci, (2000);45:1509-1516. Tougas G, “TheAutonomic Nervous System in Functional Bowel Disorders”, Gut,(2000);47(Suppl IV):iv78-iv80. Guyton A C, et al., “Propulsion andMixing of Food in the Alimentary Tract”, Textbook of Medical Physiology,10^(th) ed. Philadelphia: W. B. Saunders and Company, 200:728-737.Guyton A C, et al., “Secretory Functions of the Alimentary Tract”,Textbook of Medical Physiology, 10^(th) ed. Philadelphia: W. B. Saundersand Company, 200:738-753. Schwartz M P, et al., “Human Duodenal MotorActivity in Response to Acid and Different Nutrients”, Dig Dis Sci,(2001);46:1472-1481. Schwartz M P, et al., “Chemospecific Alterations inDuodenal Perception and Motor Response in Functional Dyspepsia”, Am JGastroenterol, (2001);96:2596-2602.

ERM involves pacing and thereby regulating the timing and the volume ofpancreatic exocrine secretion and bile delivered to the intraluminalcontents of the duodenum. In one embodiment, this is accomplished with asmall, laparoscopically implantable and programmable medical devicecalled a physiologic enteric pacing device. Three leads are positionedintra-abdominally and then connected to a subcutaneous, programmablepulse generator. A pacing lead may be placed on the anterior vagal trunkand another pacing lead may be placed on the posterior vagal trunk. Oneor more intra-abdominal electrode, i.e. blocking electrodes, may beplaced on the vagus nerve proximal to the pacing leads.

An additional embodiment of the present invention pertains to treatingat least one of a plurality of gastrointestinal disorders of a patientby electrically stimulating a vagus nerve of the patient at astimulation site proximal to at least one site of vagal innervation of agastrointestinal organ. The electrical stimulation includes applying astimulation signal at the stimulation site. A proximal electricalblocking signal is applied to the vagus nerve at a proximal blockingsite proximal to the stimulation site. The proximal blocking signal isselected to at least partially block nerve impulses proximal to theproximal blocking site.

The invention further includes a treatment apparatus having astimulation electrode adapted for placement on a nerve of a patient at astimulation site and a stimulation signal generator for generating astimulation signal at the stimulation electrode and selected toelectrically stimulate a nerve to induce bi-directional propagation ofnervous impulses in a stimulated nerve. The apparatus includes ablocking member for placement on the nerve at a blocking site andcreating localized conditions at the blocking site that at leastpartially diminish transmission of nerve impulses past the blockingsite.

A still further embodiment of the present invention includes a methodfor treating at least one of a plurality of disorders of a patient wherethe disorders are associated with a gastrointestinal tract of a patientwhere the disorders are characterized at least in part by hyper-tonalvagal activity innervating at least one of a plurality of alimentarytract organs of the patient at an innervation site. The method includesapplying a neural conduction block to a vagus nerve of the patient at ablocking site proximal to the innervation site. The neural conductionblock is selected to at least partially block nerve impulses on thevagus nerve distal to the blocking site.

A yet further embodiment pertains to a treatment apparatus having anelectrically controllable neural conduction electrode adapted to beplaced on a vagus nerve of a patient at a blocking site proximal to aninnervation site. A blocking signal generator generates a blockingsignal selected to at least partially block nerve impulses on the vagusnerve distal to the blocking site.

A still additional embodiment of the present invention includes a methodfor treating at least one of a plurality of disorders of a patient byelectrically stimulating a vagus nerve at a stimulation site with astimulation signal selected to have a therapeutic effect on a targetorgan. An electrical blocking signal is applied to the vagus nerve at ablocking site on a side of said stimulation site opposite the targetorgan. The blocking signal is selected to at least partially block nerveimpulses to a second organ on a side of said blocking site opposite thestimulation site. In specific examples, the target organ may begastrointestinal or central nervous with the other organ beingcardio-respiratory.

IV. BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a schematic representation of a gastric-emptying feedback loopwith a patient-controlled stimulator for stimulating an organ of theloop;

FIG. 2 is a view similar to FIG. 1 with an automatic controllerreplacing the patient-controller of FIG. 1 and with feedback circuits tothe automatic controller schematically represented;

FIG. 3 is a schematic illustration of an alimentary tract (GI tract plusnon-GI organs such as the pancreas and liver) and its relation to vagaland enteric innervation;

FIG. 4 is the view of FIG. 3 showing the application of a pacingelectrode according to an embodiment of the present invention;

FIG. 5 is a schematic representation of pacing system;

FIG. 6 is the view of FIG. 4 showing the application of a nerveconduction block electrode proximal to the pacing electrode;

FIG. 7 is the view of FIG. 6 showing the application of a nerveconduction block electrode distal to the pacing electrode; and

FIG. 8 is the view of FIG. 3 showing the application of a nerveconduction block electrode according to an embodiment of the presentinvention.

V. DESCRIPTION OF THE PREFERRED EMBODIMENT

With reference now to the various drawing figures in which identicalelements are numbered identically throughout, a description of thepreferred embodiment of the present invention will now be described.

A. Invention of Parent Application

FIGS. 1 and 2 and the description which follow are from theaforementioned U.S. patent application Ser. No. 10/358,093 filed Feb. 3,2003 filed Feb. 3, 2003 and entitled “Method and Apparatus for Treatmentof Gastroesophageal Disease (GERD)”.

With initial reference to FIG. 1, a gastric emptying feedback loop isshown schematically for ease of illustration. The feedback loopillustrates a patient's stomach S which is provided with food from theesophagus E. A lower esophageal sphincter LES is shown positionedbetween the esophagus E and the stomach S. The lower esophagealsphincter normally provides control of reflux of stomach contents intothe esophagus E.

On a proximal or lower end of the stomach S the stomach discharges intothe superior duodenum D which is an upper portion of the intestines. Thesuperior duodenum D and the stomach S are separated by a pyloric valvePV which opens to permit gastric emptying from the stomach into theduodenum D.

Also schematically illustrated in FIG. 1 are nerve paths N providingsignal flow paths from both the superior duodenum D and the stomach S tothe brain B. An efferent Vagal nerve VN connects the brain B to thepancreas P of the patient. A conduit (pancreatic duct PD) extends fromthe pancreas P and discharges into the superior duodenum D.

The presence of food contents within the duodenum D (such contents beingreferred to as “chyme”) may prevent passage of gastric content of thestomach S past the pyloric valve PV into the duodenum D. As long as suchgastric contents cannot be passed into the duodenum D, such contents canbe forced retrograde past the lower esophageal sphincter LES and intothe esophagus E creating the symptoms and discomfort of GERD. Thecontents discharging from the stomach S into the duodenum D are acidic(and high osmolality) and reside in the duodenum D until pH is elevated(close to a neutral pH of 6-7) and osmolality is normalized.

The elevation of pH and reduction of osmolality of chyme in the duodenumD results from exocrine secretion being administered from the pancreas Pand from bile from the liver into the duodenum D. This raises the pH andlowers the osmolality of the duodenum D content permitting dischargefrom the duodenum D and thereby permitting gastric emptying across thepyloric valve PV.

According to the present invention gastroesophageal reflux disease(GERD) results from a derangement of the feedback loops involved inupper GI digestion and motility control. This problem encompassesreceptors and reflexes that regulate the propulsive contractions of thestomach, upper duodenum and biliary tree and the secretions of theexocrine pancreas. The interaction of these receptors and reflexescontrol gastric emptying (by coordinating gastric propulsivecontractions and sphincter [primarily pyloric] tone) and regulate the pHand osmolality of the chyme in the duodenum. This chemo-regulation ismediated through control of bile delivery and stimulation of secretionby the exocrine pancreas of fluid delivered to the superior duodenum.Chey et al., “Neural Hormonal Regulation of Exocrine PancreaticSecretion”, Pancreatology, pp. 320-335 (2001).

Normally, ingestate delivered to the stomach is mixed by low intensitygastric mixing contractions with the enzymatic, ionic, includinghydrogen ion (H⁺), and water secretions of the glands of the stomach.When the material is adequately reduced in size and is a smoothconsistency, the fluid, now called chyme, is delivered to the ampulla ofthe small intestine by the much stronger propulsive, or emptying,contractions of the stomach coupled with transitory relaxation of thepyloric sphincter. This material is at a very low pH (about 2) and highosmolality, which activates receptors, including those for H⁺ andosmotic pressure, which are abundant in the wall of the ampulla. Thisreceptor activation initiates the series of reflexes that causepancreatic exocrine secretion to be delivered into the superior duodenumand ampulla. This fluid contains digestive enzymes, water and bufferingcompounds to raise the pH, and reduce the osmolality, of the chyme.

Once a neutral pH and physiological osmolality are achieved, thenpropulsive contractions in the superior duodenum move the chyme out ofthe superior portion into the length of the duodenum; At which point thestretch and baro-receptors in the ampulla allow the pyloric sphincter torelax and another bolus of gastric contents is delivered into theampulla by the peristaltic gastric emptying contractions. This material,at a very low pH (less than 2), activates hydrogen ion (H⁺) on receptorsof the ampulla (upper most portion of the duodenum) causing thepancreatic fluids to be delivered to the material in the ampullarestarting the cycle as described above. Chapter 3, “The Stomach”,Gastrointestinal System, 2^(nd) Ed., M. S. Long editor, Mosby Publisher,London (2002).

If the control system is down regulated by, for example, by increased pHof gastric contents entering the ampulla, feedback may thereby bereduced from the H⁺ receptors in the duodenum that stimulate pancreaticexocrine secretion and bile delivery to the duodenum, then movement ofchyme from the superior duodenum is delayed, causing delay of gastricemptying. Mabayo, et al., “Inhibition of Food Passage by Osmeprazole inthe Chicken”, European J. of Pharmacology, pp. 161-165 (1995).

In GERD, this reflex is inhibited in such a way that the stomach emptiesmore slowly so that the gastric emptying contractions force gastriccontents to flow retrograde into the esophagus. This is a result of thesituation in which the gastric emptying contractions are vigorous butmust operate against a contracted pyloric sphincter. These vigorousperistaltic contractions eventually begin to force gastric contents toflow retrograde into the esophagus because of the inherent imbalancebetween a very strong pyloric sphincter and a much weakergastroesophageal sphincter. The delay in gastric emptying is directlyrelated to a slow down in the transport of chyme out of the ampulla andsuperior duodenum. The drugs used to treat this disease raise pH furtherdampening the hydrogen-receptor-pancreatic secretion loop, furtherdelaying gastric emptying. Benini, “Gastric Emptying and DyspepticSymptoms in Patients with Gastroesophageal Reflux”, Amer. J. ofGastroenterology, pp. 1351-1354 (1996).

The present invention is directed towards reestablishing the linkbetween gastric emptying and pancreatic secretion delivery, therebyaddressing the main pathology of this disease by shortening chymeresidence time in the superior duodenum so that intestinal contents moveinto the distal digestive tract in a more normal manner. According to afirst embodiment, this is done by stimulating the H+ ion receptors or bystimulation of the pancreas directly or via its parasympatheticinnervation (pre-ganglionic Vagal nerves). Stimulation of pancreaticexocrine secretion has been shown by direct stimulation of the thoracicvagus nerves in dogs. Kaminski et al., “The Effect of Electrical VagalStimulation on Canine Pancreatic Exocrine Function”, Surgery, pp.545-552 (1975). This results in a more rapid (normal) neutralization ofchyme in the ampulla, allowing it move down the duodenum more quickly sothat gastric emptying is returned to a more normal pace.

Acidity (pH) can be assessed by measuring bicarbonate. It will beunderstood that references to −H includes such indirect measurements.Also, effects of the therapy described herein can be assessed and/orcontrolled by measuring an indication of pancreatic exocrine secretionor bile (e.g., HCO₃ ⁻).

An alternative embodiment uses gastrocopic delivery of a paralyzingagent (e.g. botulism toxin) to the pyloric valve along with use of H2antagonists or PPI's to manage the acidity of the chyme reaching theduodenum.

As an additional alternative to pancreatic stimulation, the gall bladdercan be stimulated to encourage bile movement into the duodenum. Shownschematically in the figures, the gall bladder GB resides below theliver L. The gall bladder is connected to the small intestine(specifically the duodenum D) via a bile duct BD. The bile duct BD candischarge directly into the duodenum D or via the pancreatic duct PD asshown. The bile can normalize the chyme to accelerate duodenal emptying.Bile consists of bile acids (detergents that emulsify lipids),cholesterol, phospholipids, electrolytes such as (Na⁺, K⁺, Ca⁺², Cl⁻,HCO₃ ⁻) and H₂O. Chapter 4, “The Liver and Biliary Tract”,Gastrointestinal System, 2^(nd) Ed., M. S. Long editor, Mosby Publisher,London (2002). The gall bladder GB or bile duct can be stimulatedindirectly via stimulation of the vagal nerve VN or directly stimulatedby an electrode 11 (shown in phantom lines).

As illustrated in the figures, an electrical stimulator 10, 20 which maybe implanted is provided which alternatively may be directly connectedto the Vagal nerve VN or the pancreas P to stimulate the pancreasdirectly or indirectly to excrete exocrine into the duodenum D (or moredistally into the small intestine—e.g., into the jejunum) and increasethe pH of chyme in the duodenum D as described. Alternatively, the samecan be done to promote bile release. The frequency may be varied tomaximize the response and selectively stimulate exocrine instead ofendocrine secretions. Rösch et al., “Frequency-Dependent Secretion ofPancreatic Amylase, Lipase, Trypsin, and Chymotrypsin During VagalStimulation in Rats”, Pancreas, pp. 499-506 (1990). See, also, Berthoudet al., “Characteristics of Gastric and Pancreatic Reponses to VagalStimulation with Varied Frequencies: Evidence for Different FiberCalibers?”, J. Auto. Nervous Sys., pp. 77-84 (1987) (showedfrequency-response relationship with insulin, i.e., significantly lessinsulin was released at lower frequencies—2 Hz v. 8 Hz—also,frequency-response curves evidenced distinctly different profiles forgastric, pancreatic and cardiovascular responses.) Slight insulinrelease can maximize pancreatic exocrine secretion. Chey et al., “NeuralHormonal Regulation of Exocrine Pancreatic Secretion”, Pancreatology,pp. 320-335 (2001).

With a patient control stimulation as shown in FIG. 1, the patient mayactivate the stimulator 10 by remote transmitter to stimulate anelectrical charge either after eating (e.g., about 60 to 90 minutesafter eating) or on onset of GERD symptoms. It will be appreciated thatthere are a wide variety of nerve stimulators and organ stimulatorsavailable for implantation and are commercially available and whichinclude connectors for connecting directly to nerves.

FIG. 2 illustrates an additional embodiment where the patient activatedloop is replaced with an automatic loop having a programmable stimulator20 which receives as an input signals from sensors in the duodenum tomeasure pH, osmolality or strain (e.g., from baro-sensors) on theduodenum indicating filling or may measure acidity in the esophagus orstrain on the lower esophageal sphincter LES or stomach S all of whichmay be provided to the implantable controller 20 which can be providedwith desirable software to process the incoming signals and generate astimulating signal to either the vagal nerve, the pancreas P or theduodenum D (or jejunum) directly in response to such received signals.It will be appreciated that stimulators and controllers are well withinthe skill of the art. U.S. Pat. No. 5,540,730 teaches a neurostimulatorto stimulate a vagus nerve to treat a motility disorder. U.S. Pat. No.5,292,344 teaches gastrointestinal sensors, including pH sensors.

B. Application of Parent Application to Treatments Other than GERD

In addition to treatment of GERD, the foregoing invention is applicableto treatment of a plurality of GI diseases associated with delayedgastric emptying or altered autonomic activity. These include functionalgastrointestinal disorders and gastroparesis. Furthermore, applicantshave determined that duodenal content impacts a plurality of motilitydisorders throughout the bowels and can diseases associated withdysmotility (e.g., irritable bowel syndrome). Accordingly it is anobject of the present invention to use the teachings of theaforementioned parent application to treat GI disorders associated withdelayed gastric emptying and abnormal intestinal transport.

C. Additional Disclosure of the Present Application

1. Enteric Innervation

FIG. 3 is a schematic illustration of an alimentary tract (GI tract plusnon-GI organs such as the pancreas and ball bladder, collectivelylabeled PG) and its relation to vagal and enteric innervation. The loweresophageal sphincter (LES) acts as a gate to pass food into the stomachS and, assuming adequate function of all components, prevent reflux. Thepylorus PV controls passage of chyme from the stomach S into theintestines I (collectively shown in the figures and including the largeintestine or colon and the small intestine including the duodenum,jejunum and ileum).

The biochemistry of the contents of the intestines I is influenced bythe pancreas P and gall bladder PG which discharge into the duodenum.This discharge is illustrated by dotted arrow A.

The vagus nerve VN transmits signals to the stomach S, pylorus PV,pancreas and gall bladder PG directly. Originating in the brain, thereis a common vagus nerve VN in the region of the diaphragm (not shown).In the region of the diaphragm, the vagus VN separates into anterior andposterior components with both acting to innervate the GI tract. InFIGS. 3, 5-8, the anterior and posterior vagus nerves are not shownseparately. Instead, the vagus nerve VN is shown schematically toinclude both anterior and posterior nerves.

The vagus nerve VN contains both afferent and efferent componentssending signals away from and to, respectively, its innervated organs.

In addition to influence from the vagus nerve VN, the GI and alimentarytracts are greatly influenced by the enteric nervous system ENS. Theenteric nervous system ENS is an interconnected network of nerves,receptors and actuators throughout the GI tract. There are many millionsof nerve endings of the enteric nervous system ENS in the tissues of theGI organs. For ease of illustration, the enteric nervous system ENS isillustrated as a line enveloping the organs innervated by the entericnervous system ENS

The vagus nerve VN innervates, at least in part, the enteric nervoussystem ENS (schematically illustrated by vagal trunk VN3 whichrepresents many vagus-ENS innervation throughout the cut). Also,receptors in the intestines I connect to the enteric nervous system ENS.Arrow B in the figures illustrates the influence of duodenal contents onthe enteric nervous system ENS as a feedback to the secretion functionof the pancreas, liver and gall bladder. Specifically, receptors in theintestine I respond the biochemistry of the intestine contents (whichare chemically modulated by the pancreao-biliary output of Arrow A).This biochemistry includes pH and osmolality.

In the figures, vagal trunks VN1, VN2, VN4 and VN6 illustrateschematically the direct vagal innervation of the GI organs of the LES,stomach S, pylorus PV and intestines I. Trunk VN3 illustrates directcommunication between the vagus VN and the ENS. Trunk VN5 illustratesdirect vagal innervation of the pancreas and gall bladder. Entericnerves ENS1-ENS4 represent the multitude of enteric nerves in thestomach S, pylorus PV, pancreas and gall bladder PG and intestines I.

While communicating with the vagus nerve VN, the enteric nervous systemENS can act independently of the vagus and the central nervous system.For example, in patients with a severed vagus nerve (vagotomy—anhistorical procedure for treating ulcers), the enteric nervous systemcan operate the gut. Most enteric nerve cells are not directlyinnervated by the vagus. Gershon, “The Second Brain”, Harper CollinsPublishers, Inc, New York, N.Y. p. 19 (1998)

In FIG. 3, the vagus VN and its trunks (illustrated as VN1-VN6) and theenteric nervous system ENS are shown in phantom lines to illustratereduced vagal and enteric nerve tone (i.e., sub-optimal nervetransmission levels). Reduced vagal and enteric tone contribute directlyto the ineffectiveness of the GI organs as well as indirectly (throughreduced pancreatic/biliary output). The reduced pancreatic/biliaryoutput is illustrated by the dotted presentation of arrow A. Aspreviously discussed, the vagus can be stimulated to stimulatepancreatic or biliary output. Therefore, the reduced output of arrow Aresults in a reduced feedback illustrated by the dotted presentation ofarrow B.

2. Enteric Rhythm Management (ERM)

The benefits of the present invention are illustrated in FIG. 4 where astimulating or pacing electrode PE is applied to the vagus VN. Whileonly one electrode is shown in FIG. 4, separate electrodes could beapplied to both the anterior and posterior vagus nerves (or to thecommon vagus or vagal branches). In a preferred embodiment, theelectrode PE is placed a few centimeters below the diaphragm andproximal to stomach and pancreo/biliary innervation. While thisplacement is presently preferred for ease of surgical access, otherplacement locations may be used.

By pacing the vagus through the pacing electrode, vagal tone isoptimized by either up- or down-regulation. With reference to theparasympathetic and enteric nervous systems, “tone” refers to basalactivity of a nerve or nervous system facilitating appropriatephysiologic response to a patient's internal environment. For example,low vagal tone implies a reduction in vagus nerve activity resulting indecreased response of the alimentary tract to ingested food. As used inthe present application, “pacing” is not limited to mean timed eventscoordinated with specifically timed physiologic events. Instead, pacingmeans any electrical stimulation of a nerve trunk to inducebi-directional propagation of nervous impulses in the stimulated nerve.

The operating effectiveness of the vagus is enhanced so that localphysiological signals generated in the enteric nervous system (or sentto the brain from the organs) are more appropriately responded to withinthe alimentary tract. Due to its innervation of the enteric nervoussystem, pacing of the vagus enhances the functional tone of the entericnervous system. By enhancing the functional tone it will be noted thatthe stimulation pacing is elevating the degree of functionality of thevagus and enteric nerves. In this context, “pacing” is not meant to meantimed pulsed coordinated with muscular contractions or synchronized withother invents. Pacing means elevating the activity level of the nerves.

Tonal enhancement of the vagus and enteric nerves is illustrated by thesolid lines for the nerves VN, ENS in FIG. 4. Vagal trunk VN5 is insolid line to illustrate enhanced tone of the many vagal nervecomponents communicating with the enteric nervous system ENS. Directvagal innervation of the LES, stomach S, pylorus PV and intestines Iremains shown as low tone indicated by phantom lines VN1, VN2, VN4, VN6.The tonal pacing described herein is not intended to trigger or drivethe muscular contractility of these organs. The stimulation is notintended to be timed to trigger contractility and is not provided withan energy level sufficient to drive peristaltic contractions. Instead,these functions remain controlled by the central and enteric nervessystems. The enhanced nerve tone provided by the present inventionpermits these functions to occur.

Pacing to enhance vagal tone is not initiated in response to any sensesevent (or in anticipation of an immediate need to GI activity). Instead,the pacing can be done intermittently over the day to provide anenhanced level of operating functionality to the vagus. By way ofnon-limiting example, the stimulation pacing can be done during awakehours. For example, every ten minutes, pacing signals can be sent to thepacing electrodes. The pacing signals have a duration of 30 seconds witha current of 4 mA, a frequency of 12 Hz and an impulse duration of 2msec. These parameters are representative only. A wide range of signalparameters may be used to stimulate the vagus nerve. Examples of theseare recited in the afore-referenced literature

As will be further discussed, the present invention permits ERM to beuniquely designed and modified by an attending physician to meet thespecific needs of individual patients. For example, pacing can belimited to discrete intervals in the morning, afternoon and evening withthe patient free to coordinate meals around these events.

In addition to enhancing vagal and enteric tone directly, the pacingalso enhances the pancreatic and biliary output for the reasonsdiscussed above. Namely, while ERM does not drive muscular events overnerve trunks VN1, VN2, VN4, VN6, the enhanced tone stimulatespancreo-biliary output over trunk VN5 (illustrated by the solid line ofVN5 in FIG. 4). This enhanced output is illustrated as solid arrow A′ inFIG. 4. As a consequence there is a greater feedback to the intestinalreceptors as illustrated by solid arrow B′ in FIG. 4. This enhancedbiochemistry feedback further enhances the tone of the enteric nervoussystem ENS.

3. Implantable Pacing Circuit

A representative pacing circuit 100 is schematically shown in FIG. 5.Similar to cardiac pacing devices, an implantable controller 102contains an induction coil 104 for inductive electrical coupling to acoil 106 of an external controller 108. The implantable controller 102includes anterior and posterior pulse generators 110, 112 electricallyconnected through conductors 114, 116 to anterior and posterior pacingelectrodes 118, 120 for attachment to anterior and posterior trunks,respectively, of the vagus nerve VN. The implantable controller 102 alsoincludes a battery 122 and a CPU 124 which includes program storage andmemory. The timing and parameters of the pulse at the electrodes 118,120 can be adjusted by inductively coupling the external controller 108to the implantable controller 102 and inputting pacing parameters (e.g.,pulse width, frequency and amplitude).

While a fully implantable controller 102 is desirable, it is notnecessary. For example, the electrodes 118, 120 can be implantedconnected to a receiving antenna placed near the body surface. Thecontrol circuits (i.e., the elements 124, 110, 112 and 108) can behoused in an external pack worn by the patient with a transmittingantenna held in place on the skin over the area of the implantedreceiving antenna. Such a design is forward-compatible in that theimplanted electrodes can be later substituted with the implantablecontroller 102 at a later surgery if desired.

Although not shown in FIG. 5, the controller 102 can also includecircuits generating nerve conduction block signals (as will bedescribed) which connect to electrodes which may be positioned on anerve proximally, distally (or both) of the electrodes 118, 120.

4. Nerve Conduction Block

FIG. 6 shows an alternative embodiment using a nerve conduction blockingelectrode PBE proximal to the pacing electrode for providing aconduction block. A nerve block is, functionally speaking, a reversiblevagotomy. Namely, application of the block at least partially preventsnerve transmission across the site of the block. Removal of the blockrestores normal nerve activity at the site. A block is any localizedimposition of conditions that at least partially diminish transmissionof impulses.

The vagal block may be desirable in some patients since unblocked pacingmay result in afferent vagal and antidromic efferent signals havingundesired effect on organs innervated by the vagus proximal to the GItract (e.g., undesirable cardiac response). Further, the afferentsignals of the pacing electrode PE can result in a central nervoussystem response that tends to offset the benefits of the pacingelectrode on the ENS and pancreo/biliary function. a thereby reducingthe GI and enteric rhythm management effectiveness of vagal pacing.

The block may be intermittent and applied only when the vagus is pacedby the pacing electrode PE. The preferred nerve conduction block is anelectronic block created by a signal at the vagus by an electrode PBEcontrolled by the implantable controller (such as controller 102 or anexternal controller). The nerve conduction block can be any reversibleblock. For example, cryogenics (either chemically or electronicallyinduced) or drug blocks can be used. An electronic cryogenic block maybe a Peltier solid-state device which cools in response to a current andmay be electrically controlled to regulate cooling. Drug blocks mayinclude a pump-controlled subcutaneous drug delivery.

With such an electrode conduction block, the block parameters (signaltype and timing) can be altered by a controller and can be coordinatedwith the pacing signals to block only during pacing. A representativeblocking signal is a 500 Hz signal with other parameters (e.g., timingand current) matched to be the same as the pacing signal). While analternating current blocking signal is described, a direct current(e.g., −70 mV DC) could be used. The foregoing specific examples ofblocking signals are representative only. Other examples and ranges ofblocking signals are described in the aforementioned literature (allincorporated herein by reference). As will be more fully described, thepresent invention gives a physician great latitude in selected pacingand blocking parameters for individual patients.

Similar to FIG. 4, the vagus VN and enteric nervous system ENS in FIG. 6distal to the block PBE are shown in solid lines to illustrate enhancedtone (except for the direct innervation VN1, VN2, VN4, VN6 to the GItract organs). Similarly, arrows A′, B′ are shown in solid lines toillustrate the enhanced pancreo-biliary output and resultant enhancedfeedback stimulation to the enteric nervous system ENS. The proximalvagus nerve segment VNP proximal to the block PBE is shown in phantomlines to illustrate it is not stimulated by the pacing electrode PEwhile the blocking electrode PBE is activated.

5. Proximal and Distal Blocking

FIG. 7 illustrates the addition over FIG. 6 of a nerve conductive blockDBE distal to the pacing electrode PE. The proximal block PBE preventsadverse events resulting from afferent signals and heightens the GIeffectiveness by blocking antidromic interference as discussed withreference to FIG. 6.

In FIG. 7, the distal block DBE is provided in the event there is adesire to isolate the pacing effect of electrode PE. For example, aphysician may which to enhance the vagus and enteric activity in theregion proximal to the duodenum but may wish to avoid stimulatingpancreo-biliary output. For example, a patient may have a GI problemwithout apparent colon dysfunction (e.g., gastroparesis functionaldyspepsia without bowel symptoms). Placing the distal block DBE on abranch of the vagus between the pacing electrode PE and the pancreas andgall bladder PG prevents increased pancreo-biliary output and resultantfeedback (illustrated by dotted arrows A and B in FIG. 7 and dotteddistal vagal nerve segment VND and vagal trunk VN5).

6. Blocking as an Independent Therapy

FIG. 8 illustrates an alternative embodiment of the invention.

In certain patients, the vagus nerve may be hyperactive contributing todiarrhea-dominant IBS. Use of a blocking electrode alone in the vaguspermits down-regulating the vagus nerve VN, the enteric nervous systemENS and pancreo-biliary output. The block down-regulates efferent signaltransmission. In FIG. 8, the hyperactive vagus is illustrated by thesolid line of the proximal vagus nerve segment VNP. The remainder of thevagus and enteric nervous system are shown in reduced thickness toillustrate down-regulation of tone. The pancreo-biliary output (andresulting feedback) is also reduced. In FIG. 8, the blocking electrodeBE is shown high on the vagus relative to the GI tract innervation(e.g., just below the diaphragm), the sole blocking electrode could beplaced lower (e.g., just proximal to pancreo/biliary innervation VN5).

7. Application to Obesity

The foregoing discussion has been described in a preferred embodiment oftreating FGIDs, gastroparesis and GERD. Obesity is also treatable withthe present invention.

Recent literature describes potential obesity treatments relative to guthormone fragment peptide YY₃₋₃₆. See, e.g., Batterham, et al.,“Inhibition of Food Intake in Obese Subjects by Peptide YY3-36”, NewEngland J. Med., pp. 941-948 (Sep. 4, 2003) and Korner et al., “To Eator Not to Eat—How the Gut Talks to the Brain”, New England J. Med., pp.926-928 (Sep. 4, 2003). The peptide YY₃₋₃₆ (PPY) has the effect ofinhibiting gut motility through the phenomena of the ileal brake. Vagalafferents create a sensation of satiety.

The present invention can electrically simulate the effects of PPY byusing the vagal block to down-regulate afferent vagal activity to createa desired sensation of satiety. Since the down-regulation does notrequire continuous blocking signals, the beneficial efferent signals arepermitted.

8. Application to Other Therapies

There are numerous suggestions for vagal pacing or stimulation to treata wide variety of diseases. For example, U.S. Pat. No. 5,188,104 datedFeb. 23, 1993 describes vagal stimulation to treat eating disorders.U.S. Pat. No. 5,231,988 dated Aug. 3, 1993 describes vagal stimulationto treat endocrine disorders. U.S. Pat. No. 5,215,086 dated Jun. 1, 1993describes vagal stimulation to treat migraines. U.S. Pat. No. 5,269,303dated Dec. 14, 1993 describes vagal stimulation to treat dementia. U.S.Pat. No. 5,330,515 dated Jul. 19, 1994 describes vagal stimulation totreat pain. U.S. Pat. No. 5,299,569 dated Apr. 5, 1994 describes vagalstimulation to treat neuropsychiatric disorders. U.S. Pat. No. 5,335,657dated Aug. 9, 1994 describes vagal stimulation to treat sleep disorders.U.S. Pat. No. 5,707,400 dated Jan. 13, 1998 describes vagal stimulationto treat refractory hypertension. U.S. Pat. No. 6,473,644 dated Oct. 29,2002 describes vagal stimulation to treat heart failure. U.S. Pat. No.5,571,150 dated Nov. 5, 1996 describes vagal stimulation to treatpatients in comas. As previously described, U.S. Pat. No. 5,540,730dated Jul. 30, 1996 describes vagal stimulation to treat motilitydisorders and U.S. Pat. No. 6,610,713 dated Aug. 26, 2003 describesvagal stimulation to inhibit inflammatory cytokine production. All ofthe foregoing U.S. patents listed in this paragraph are incorporatedherein by reference.

All of the foregoing suffer from undesired effects of vagal pacing oncardiovascular, gastrointestinal or other organs. Nerve conductionblocking permits longer pulse durations which would otherwise haveadverse effects on other organs such as those of the cardiovascular orgastrointestinal systems. In accordance with the present invention, allof the foregoing disclosures can be modified by applying a blockingelectrode and blocking signal as disclosed herein to prevent adverseside effects. By way of specific example, pacing a vagus nerve in thethoracic cavity or neck combined with a blocking electrode on the vagusnerve distal to the pacing electrode can be used to treatneuropsychiatric disorders (such as depression and schizophrenia) andParkinson's and epilepsy and dementia. In such treatments, the blockingelectrode is placed distal to the stimulating electrode 25 shown inFIGS. 4 and 2, respectively, of each of U.S. Pat. Nos. 5,269,303 and5,299,569. The present invention thereby enables the teachings of theafore-referenced patents listed in foregoing two paragraphs.

As described, the parameters of the stimulating and blocking electrodescan be inputted via a controller and, thereby, modified by a physician.Also, FIG. 2 illustrates a feedback for controlling a stimulatingelectrode. Feedbacks for stimulating electrodes are also described inthe patents incorporated by reference. The blocking electrode can alsobe controlled by an implanted controller and feedback system. Forexample, physiologic parameters (e.g., heart rate, blood pressure, etc.)can be monitored. The blocking signal can be regulated by the controllerto maintain measured parameters in a desired range. For example,blocking can be increased to maintain heart rate within a desired raterange during stimulation pacing.

9. Opportunity for Physician to Alter Treatment for Specific Patient

Gastrointestinal disorders are complex. For many, the precise mechanismis of the disorder is unknown. Diagnosis and treatment are ofteniterative processes. The present invention is particularly desirable fortreating such disorders.

Use of proximal and distal blocking electrodes in combination with oneor more pacing electrode permits a physician to alter an operatingpermutation of the electrodes. This permits regional and local up- ordown-regulation of the nervous system and organs. Further, pacingparameters (duty cycle, current, frequency, pulse length) can all beadjusted. Therefore, the treating physician has numerous options toalter a treatment to meet the needs of a specific patient.

In addition, a physician can combine the present invention with othertherapies (such as drug therapies like prokinetic agents).

With the foregoing detailed description of the present invention, it hasbeen shown how the objects of the invention have been attained in apreferred manner. Modifications and equivalents of disclosed conceptssuch as those which might readily occur to one skilled in the art, areintended to be included in the scope of the claims which are appendedhereto.

1. A method for treating a gastrointestinal disorder characterized bydysmotility of a gastrointestinal organ comprising: electricallystimulating a vagus nerve of a patient having the gastrointestinaldisorder by applying a first electrode on the vagus nerve at astimulation site proximal to at least one site of vagal innervation of agastrointestinal organ and below a diaphragm of said patient, saidelectrical stimulation comprising applying a stimulation signal at saidsite intermittently, wherein said stimulation signal is selected toenhance pancreo-biliary output; and applying a second electrode todeliver an electrical blocking signal intermittently to said vagus nerveat a site proximal to said stimulation site, said electrical stimulationfurther comprising applying said blocking signal to said proximal sitewherein said blocking signal is selected to a) block nerve impulsesproximal to said proximal blocking site; b) allow recovery of the nerveafter cessation of the blocking signal; c) have a frequency of at least500 Hz; and d) at least partially block afferent signals proximal to thestimulation site; and applying a third electrode to deliver a distalelectrical blocking signal to said vagus nerve at a distal blocking sitedistal to said stimulation site, said electrical stimulation furthercomprising applying said distal electrical blocking signal to saiddistal blocking site with said distal electrical blocking signalselected to at least partially block transmission of efferent signalsdistal to said distal blocking site.
 2. The method of claim 1, whereinthe stimulation signal is applied during waking hours.
 3. The method ofclaim 2, wherein the stimulation signal is applied once every tenminutes.
 4. The method of claim 1, wherein the stimulation signal has afrequency of 12 Hz.
 5. The method of claim 1, wherein each blockingsignal is applied concurrently with the stimulation signal.
 6. Themethod of claim 1, wherein the vagus nerve comprises an anterior, aposterior, or anterior and posterior vagus nerves.